Association of Vitamin C, Thiamine, and Hydrocortisone Infusion With Long-term Cognitive, Psychological, and Functional Outcomes in Sepsis Survivors
Authors: Shawniqua Williams Roberson, Samuel Nwosu, Erin M. Collar, Amy L. Kiehl, Fiona E. Harrison, Julie Bastarache, Jo Ellen Wilson, Matthew F. Mart, Jonathan E. Sevransky, E. Wesley Ely, Christopher J. Lindsell, James C. Jackson, Katherine Nugent, Christine Spainhour, Carmen Polito, Brooks Moore, Lovie Negrin, Akram Khan, Bory Kea, Olivia Krol, Ebaad Haq, Vincent Pinkert, Kelly Nguyen, Samuel M Brown, Joseph Bledsoe, Ithan Peltan, Darrin Applegate, Brent Armbuster, Quinn Montgomery, Katie Brown, Austin Daw, Michelle Gong, Michael Aboodi, Jen-Ting (Tina) Chen, Aluko Hope, Swarna Gummadi, Brenda Lopez, Jeremiah Hinson, David Hager, Erin Ricketts, Johnathan Clare, Breana McBryde, Casey M. Clements, Ognjen Gajic, Rahul Kashyap, Derek Vanmeter, Laurence Busse, Mary McBride, Adit Ginde, Marc Moss, Lani Finck, Michelle Howell, Jeffrey McKeehan, Carrie Higgins, Aaron Barksdale, Dan Kalin, Derek Kruse, Katlyn Hilz, Nida Qadir, Steven Y. Chang, Rebecca Beutler, Andrea Tam, Estelle S. Harris, Scott T. Youngquist, Elizabeth A. Middleton, Ervin Davidov, Amber Plante, Justin Belsky, Jonathan Siner, Charles Wira, Carolyn Brokowski, Jay Steingrub, Howard Smithline, Sherell Thorton-Thompson, Alpha Fowler, Stephen Miller, Kyle Narron, Michael A. Pusckarich, Matthew E. Prekker, Audrey Hendrickson, James Quinn, Jennifer Wilson, Joseph Levitt, Rosen Mann, Anita Visweswaran, Nina Gentile, Nathaniel Marchetti, Hannah Reimer, Faheem Guirgis, Lisa Jones, Lauren Black, Morgan Henson, Nuala J. Meyer, John C. Greenwood, Caroline Ittner, Emanuel Rivers, Namita Jayaprakash, Jayna Gardner-Gray, Gina Hurst, Jacqueline Pflaum, Anja Kathrin Jaehne, Jasreen Gill, Aaron Cook, David R Janz, Derek Vonderhaar, Connie Romaine, R. Gentry Wilkerson, Michael T. McCurdy, Dana Beach, Kyra Lasko, Richard Gill, Katherine Price, Lisa Dickson, Abhijit Duggal, Sharon E. Mace, R. Duncan Hite, Andrei Hastings, Jason Haukoos, Ivor Dougla, Stacy Trent, Carolynn Lyle, Alicia Cupelo, Stephanie Gravitz, Terra Hiller, Judy Oakes, Frank LoVecchio, Pedro Quiroga, Shiloh Danley, Mary Mulrow, Amanda Encinas, Andrew Goodwin, Gregory Hall, Abigail Grady, Matthew Exline, Thomas Terndrup, Sonal Pannu, Emily Robart, Sarah Karow, D. Clark Files, Lane Smith, Kevin Gibbs, Lori Flores, Stephen M. Pastores, David J. Shaz, Natalie Kostelecky, Chad Chase, Elizabeth (Liz) Wilkins, David Gaieski, Michael Baram, Daniel Schwegler, Nicole Renzi, Jarrod M. Mosier, Cameron Hypes, Elizabeth Salvagio Campbell, Michael Hooper, Joshua Sill, Kate Mitchell, Kristin Hudock, Michael Lyons, Kari Gordner, Yousef Ahmad, Autumn Studer, Jacqueline Davis, Matthew Barrett, Jason Nomura, Jennifer Knox, Pauline Park, Ivan Co, Jakob McSparron, Robert Hyzy, Kelli McDonough, Sinan Hanna, Wesley H. Self, Matthew W. Semler, Margaret Hays, Racquel Bartz, Alexander Limkakeng, Katherine Sweeney, Rachael Woodburn, Munish Goyal, Akram Zaaqoq, Theresa Moriarty, John Oropello, Ziya Zhang
Journal: JAMA Network Open (2023)

Importance Sepsis is associated with long-term cognitive impairment and worse psychological and functional outcomes. Potential mechanisms include intracerebral oxidative stress and inflammation, yet little is known about the effects of early antioxidant and anti-inflammatory therapy on cognitive, psychological, and functional outcomes in sepsis survivors. Objective To describe observed differences in long-term cognitive, psychological, and functional outcomes of vitamin C, thiamine, and hydrocortisone between the intervention and control groups in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized clinical trial. Design, Setting, and Participants This prespecified secondary analysis reports the 6-month outcomes of the multicenter, double-blind, placebo-controlled VICTAS randomized clinical trial, which was conducted between August 2018 and July 2019. Adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction who survived to discharge or day 30 were recruited from 43 intensive care units in the US. Participants were randomized 1:1 to either the intervention or control group. Cognitive, psychological, and functional outcomes at 6 months after randomization were assessed via telephone through January 2020. Data analyses were conducted between February 2021 and December 2022. Interventions The intervention group received intravenous vitamin C (1.5 g), thiamine hydrochloride (100 mg), and hydrocortisone sodium succinate (50 mg) every 6 hours for 96 hours or until death or intensive care unit discharge. The control group received matching placebo. Main Outcomes and Measures Cognitive performance, risk of posttraumatic stress disorder and depression, and functional status were assessed using a battery of standardized instruments that were administered during a 1-hour telephone call 6 months after randomization. Results After exclusions, withdrawals, and deaths, the final sample included 213 participants (median [IQR] age, 57 [47-67] years; 112 males [52.6%]) who underwent long-term outcomes assessment and had been randomized to either the intervention group (n = 108) or control group (n = 105). The intervention group had lower immediate memory scores (adjusted OR [aOR], 0.49; 95% CI, 0.26-0.89), higher odds of posttraumatic stress disorder (aOR, 3.51; 95% CI, 1.18-10.40), and lower odds of receiving mental health care (aOR, 0.38; 95% CI, 0.16-0.89). No other statistically significant differences in cognitive, psychological, and functional outcomes were found between the 2 groups. Conclusions and Relevance In survivors of sepsis, treatment with vitamin C, thiamine, and hydrocortisone did not improve or had worse cognitive, psychological, and functional outcomes at 6 months compared with patients who received placebo. These findings challenge the hypothesis that antioxidant and anti-inflammatory therapy during critical illness mitigates the development of long-term cognitive, psychological, and functional impairment in sepsis survivors. Trial Registration ClinicalTrials.gov Identifier: NCT03509350